Drug-resistant epilepsy is a serious condition that negatively impacts patients' quality of life. Those with drug-resistant epilepsy are at a higher risk for sudden unexpected death in epilepsy (SUDEP). The risk factors associated with SUDEP, including frequent generalized tonic-clonic seizures, antiepileptic drug (AED) polytherapy, and common nocturnal seizures, are also factors present in those with drug-resistant epilepsy (Pack A M., SUDEP, What Are the Risk Factors? Do Seizures or Antiepileptic Drugs Contribute to an Increased Risk?, Epilepsy Currents, Vol. 12, No. 4 (July/August) 2012 pp. 131-132). The risk of SUDEP in those with drug-resistant epilepsy can exceed 5% per decade (Devinsky O. N Engl J Med. 2011; 365(19):1801-11). Most patients with drug-resistant epilepsy, despite trials of multiple combinations of AEDs, have no Food and Drug Administration (FDA)-approved treatment options left. CDKL5 and SCN1A related epilepsies are rare epilepsies commonly associated with drug-resistant epilepsy.
CDKL5 is a gene that produces the cyclin-dependent kinase-like 5 (CDKL5) protein that is primarily expressed in the brain, thymus, and testes. The gene is composed of 24 exons; exons 2-11 code for the catalytic domain whereas exons 12-18 code for the carboxy-terminus. In mice, the expression profile suggests that the CDKL5 protein is involved in neuronal maturation (Rusconi et al., J Biol Chem., 2008; 283(44):30101-11). CDKL5 phosphorylates the protein product of the MECP2 gene in the nucleus and likely accounts for the similarity between Rett syndrome and CDKL5 related epilepsies (Mari F., Azimonti S., Bertani I., Bolognese F., Colombo E., Caselli R., Scala E., Longo I., Grosso S., Pescucci C., Ariani F., Hayek G., Balestri P., Bergo A., Badaracco G., Zappella M., Broccoli V., Renieri A., Kilstrup-Nielsen C., Landsberger N., CDKL5 Belongs to the Same Molecular Pathway of MeCP2 and it is Responsible for the Early-Onset Seizure Variant of Rett Syndrome, Human Molecular Genetics, 2005, Vol. 14, No. 14, 1935-1946). MECP2 regulates genes associated with synapse function and maintenance. Loss of this function drives phenotype and is responsible for similarities to Rett syndrome. CDKL5 also phosphorylates DNA methyltransferase 1 (DNMT1) and amphiphysin, and interacts with Rac1 to influence actin remodeling and neuronal morphogenesis.
CDKL5 related epilepsies are X-linked genetic epileptic encephalopathies most often present in females. Males are more severely affected than females (Melani et al., Dev Med Child Neurol. 2011; 53(4):354-60). The incidence is ˜1 in 45,000 live births. Patients with CDKL5 related X-linked genetic epileptic encephalopathies exhibit early signs of poor developmental skills, (e.g., poor sucking, poor eye contact) in the first several months of life. Later, impairment of hand motor skills, lack of speech acquisition, and severe and global developmental delays become apparent (Fehr et al., Eur J Hum Genet. 2013; 21(3):266-73; Melani et al., Dev Med Child Neurol. 2011; 53(4):354-60). Eye contact and social interactions are often reduced. Many patients are never able to walk independently. CDKL5 related epilepsies are not associated with cortical atrophy or degeneration. CDKL5 deficiency causes an epileptic encephalopathy, in which epileptiform abnormalities contribute to progressive functional impairment. Epilepsy often presents with infantile spasms within the first four months of age (Mei et al., Epilepsia. 2010 April; 51(4):647-54). The average age of seizure onset is 6 weeks with more than 90% experiencing seizures in the first 3 months of life. Later, tonic-clonic seizures consisting of a vibratory tonic phase followed by a clonic phase occur and often last 2 to 4 minutes (Melani et al., Dev Med Child Neurol. 2011; 53(4):354-60). After age 3 years, seizures remit in many children while others continue to have drug-resistant epilepsy, with tonic spasms and of myoclonic seizures (Mei et al., Epilepsia. 2010 April; 51(4):647-54). The electroencephalogram findings often include slowing of the background with interictal generalized, focal or multifocal discharges. A burst-suppression pattern may be seen in younger children (Melani et al., Dev Med Child Neurol. 2011; 53(4):354-60).
SCN1A (Nav1.1) is the sodium channel al subunit gene, expressed almost exclusively in the brain. Mutations in SCN1A can cause a variety of epilepsies that range from benign febrile seizures to severe epileptic encephalopathy and Dravet syndrome (severe myoclonic epilepsy of infancy; Mulley et al., Hum Mutat. 2005; 25(6):535-42; Catterall et al., J Physiol. 20101; 588(Pt 11):1849-59). The major mechanism underlying epilepsy appears to be impairment of gamma-Aminobutyric acid (GABA) interneuron inhibitory function (Catterall et al., J Physiol. 20101; 588(Pt 11):1849-59; Yu F H., Mantegazza M., Westenbroek R E., Robbins C A., Kalume F., Burton K A., Spain W J., McKnight G S., Scheuer T., Catterall W A., Reduced Sodium Current in GABAergic Interneurons in a Mouse Model of Severe Myoclonic Epilepsy in Infancy, Nature Neuroscience, 2006, September, Vol. 9, No. 9, 1142-1149).
Dravet syndrome was initially described in 1978 as Severe Myoclonic Epilepsy of Infancy (SMEI) by Charlotte Dravet (Dravet C. Dev Med Child Neurol. 2011; 53(Suppl 2):1-6). It causes febrile and afebrile, generalized and unliateral, clonic or tonic-clonic seizures; it can also cause absence, absence-myoclonic, and complex partial seizures. Seizures typically begin in the first year of life in an otherwise normal infant. Initial seizures are often febrile status epilepticus (Dravet C., Bureau M., Oguni H., Fukuyama Y., Cokar O., Severe Myoclonic Epilepsy in Infancy: Dravet Syndrome, Adv. Neurol. (2005), 95, 71-102). Later, myoclonic, atypical absence, and partial seizures often develop. Seizures are usually drug-resistant but the severity of the epilepsy tends to diminish around puberty. Developmental delays in the second year of life and intellectual disability are present in more than 95% of patients (Chieffo D., Battaglia D., Lettori D., Del Re M., Brogna C., Dravet C., Mercuri E., Guzzetta F., Chieffo, D., Chieffo, D., Neuropsychological Development in Children with Dravet Syndrome, Epilepsy Research, (2011), 95, 86-93). Autism spectrum disorder is diagnosed in approximately 25% of patients (Genton et al., Epilepsia. 2011; 52(Suppl 2):44-9). Most patients develop cerebellar dysfunction in later childhood, manifesting as an ataxic gait disorder, dysarthria, and intention tremor (Genton et al., Epilepsia. 2011; 52(Suppl 2):44-9). The mortality rate is high. Approximately 15% of patients die by adolescence and 20% die by early adulthood (Genton et al., Epilepsia. 2011; 52(Suppl 2):44-9). SUDEP and status epilepticus are the most common causes of death.
Nonsense mutations are single-point alterations in the DNA that, when transcribed, result in conversion of a messenger ribonucleic acid (mRNA) triplet (e.g., CAG) that codes for an amino acid to a triplet (e.g., UAG) that is interpreted as a stop codon (i.e., a premature stop codon). The presence of the premature stop codon within the mRNA leads to production of a truncated, non-functional protein and consequent disease. Nonsense mutations are the basis for approximately 13% to 40% of the individual cases of most inherited disease, including CDKL5 deficiency and SCN1A deficiency (in particular, Dravet syndrome) amongst many others (Frame Katheryn, Elibri DO. The International CDKL5 Disorder Database Newsletter 1 (July 2013)).